Exercise therapy (ET) is effective as the first line of treatment for reducing pain and disability in patients with knee osteoarthritis (OA), but studies show its effects diminish considerably over time. 'Booster'intervention sessions (periodic face-to-face follow-up appointments following discharge from supervised therapy designed to review and progress the patient's home program, troubleshoot problems with the program, etc.) have been recommended to make beneficial effects endure however this recommendation has not been adequately tested. There are also indications that manual therapy (MT), manually applied treatment techniques such as joint mobilization/manipulation, manual traction, soft tissue manipulations, and passive stretching, when combined with ET, may improve the overall effectiveness of rehabilitation for reducing pain and disability, and, may significantly delay or reduce the need for total knee arthroplastic surgery and reduce medication intake in people with knee OA. However, current published evidence-based treatment guidelines indicate there is not enough data to make a definitive recommendation regarding the use of MT with ET in rehabilitation programs. Therefore, the overall aim of the project is to examine the clinical and cost-effectiveness of utilizing booster sessions in the delivery of ET, and supplementing ET with MT techniques. The study will be a multi-center, multi-national randomized clinical trial, using a 2 x 2 factorial design (factor 1 = booster vs. no booster, factor 2 = ET alone vs. ET + MT). Three hundred subjects (75 per study site) with knee OA will be randomized to one of the following groups: 1) ET - no booster, 2) ET - with booster, 3) MT + ET - no booster sessions, 4) MT + ET - with booster sessions. Clinical outcome measures (WOMAC, knee pain, global rating of change and performance-based measures of function) will be taken at baseline (prior to randomization), at the completion of the initial therapy sessions (9 weeks) and at 1 year follow-up. The primary endpoint for clinical outcome will be the WOMAC at 1 year. For the cost effectiveness analysis, the primary cost outcome will be osteoarthritis treatment costs from the societal perspective, which will include health system costs for implementing each intervention, medical/surgical costs (primary, secondary, and tertiary care costs), and personal costs to participants (travel, non-funded medications, time off work, and quality-of-life burdens). The primary effectiveness outcome measure will be quality-adjusted life-years (QALYs), derived using quality of life utilities from SF-12 scores using appropriate preference weightings for the country of origin. Cost and effectiveness values between interventions will be compared via incremental cost-effectiveness ratios, yielding incremental costs per QALY gained when a given intervention is chosen. Secondary analyses will examine cost-effectiveness from health system and from patient perspectives. Cost and effectiveness data will be obtained at 1 year and 2 year follow-ups. The 2 year follow-up will be the primary endpoint for the cost-effectiveness analysis. PUBLIC HEALTH RELEVANCE: Combining booster sessions and manual therapy techniques with exercise therapy may improve the overall effectiveness of rehabilitation over the current state of practice and may also ensure long term maintenance of the beneficial effects. The study interventions could lead to prevention or delay in disability, reduce or delay the need for total knee replacement surgery, and reduce medication intake. These beneficial effects could have a profound impact on reducing the cost of care to society and to the person with knee OA, a major cause of disability and health care cost in the United States.